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On January 16, 2019, the United States Food and Drug Administration issued a new draft Guidance entitled “ANDA Submissions –Amendments and Requests for Final Approval to Tentatively Approved ANDAs”.
This new FDA Guidance provides useful and practical information on how an ANDA applicant can timely obtain Final Approval (“FA”) when its ANDA has already received Tentative Approval (“TA”). The Guidance is generally broken down into three main sections and advises: (I) how and when to submit amendments after TA; (II) commonly submitted changes to tentatively approved ANDAs; and (III) the content of requests for FA.
(I) How and When to Submit Amendments.
The Guidance provides information on a number of issues that could arise after an ANDA has received TA and is waiting the earliest lawful date for FA that could implicate when to submit a request for FA and when to submit an amendment after TA.
- For an ANDA receiving TA less than three (3) years before the earliest lawful FA date, and that has no new data, information or other changes, the request for FA would be considered a minor amendment and should be submitted no later than three (3) months before the date on which the applicant is seeking FA.
- For an ANDA receiving TA less than three (3) years before the earliest lawful FA date but that has substantive changes, the question becomes will those changes be classified as a major or minor amendment as articulated in the Amendments Guidance. Changes to add a new facility or in the status of a facility’s compliance with GMP, for instance, would be considered a major amendment requiring an inspection and 10 months of review from the date of submission of the request for FA.
- For an ANDA having TA status for longer than three (3) years before the earliest lawful FA date, more time may be required before a request for FA is granted and the FA is issued because of changes that may have occurred since TA was granted. The Guidance recommends submission of this type of request for FA at least 10 months before the earliest lawful FA date.
- If FDA identifies deficiencies in the request for FA and communicates those deficiencies in a complete response letter, the ANDA will be placed in complete response status until the deficiencies are adequately addressed. Once the deficiencies are addressed, the FDA may reissue a TA in response to the request for FA or grant FA, as applicable.
(II) Commonly Submitted Changes to Tentatively Approved ANDAs
The Guidance also provides a non-exhaustive listing of common developments that may need to be submitted as an amendment to the tentatively approved ANDA to ensure that such an ANDA is complete and up-to-date before a request for FA is submitted. These include:
(A) Product Quality Updates – new API source; technical changes to product, process or analytical methods; updated USP chapters or monographs; updated stability data; new facilities; changes to size, shape or color of solid oral dosage form; new test methods; new submission batch data; new certificates of analysis, new packaging information; new sterilization or depyrogenation equipment or methods for sterile drug products; and updates to DMFs.
(B) Bioequivalence Updates – new in vivo or in vitro bioequivalence studies consistent with new, revised or finalized product-specific guidance.
(C) Labeling Updates – RLD labeling changes; USP chapter or monograph changes; new product quality information or information related to bioequivalence studies; omission of an indication or other aspect of labeling protected by patent or exclusivity; subsequently approved indications; statements previously carved out that are no longer patent or exclusivity protected; changes to finished dosage form packaging; and new proprietary name requests.
(D) Orange Book Listing, Patent and Exclusivity Updates – updated patent certification or statement; certification or statement to timely filed, newly listed patent for RLD; changes in certification (from PIV to PIII); litigation updates; and confirmation that RLD is identified in the Active section of Orange Book.
(III) Content of requests for FA
Finally, the Guidance advises on the content of a request for FA. The request for FA should include:
- a cover letter that identifies all changes to made to the ANDA since TA was granted; and
- a complete and accurate Form FDA 356h.
- If no changes were made to ANDA, a clear statement indicating no changes.
- For editorial or non-substantive changes, a clear statement identifying the changes and where in the ANDA those changes were made.
- For substantive new information, a clear identification of the new information, changes made in the ANDA and the location of information supporting those changes, and for FDA’s assessment of the request, supporting information commensurate with the change.
- For labeling changes, a side-by-side labeling comparison to RLD label annotating the differences with appropriate explanations.
- Statement as to whether the request for FA should be considered major or minor consistent with the Amendments Guidance criteria.